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Published on: November 17, 2018
Hypercholesterolemia induces side-specific phenotypic changes and peroxisome proliferator-activated receptor-gamma
Marie A Guerraty1, Gregory R Grant, John W Karanian
1Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia 19104, USA.
Insights
The aortic side of aortic valves, prone to sclerosis, shows a protective endothelial response to high cholesterol. This protective phenotype, identified through gene expression, persists over time in a swine model.
Area of Science:
- Cardiovascular Biology
- Endothelial Cell Biology
- Aortic Valve Disease
Background:
- Healthy aortic valve endothelium exhibits distinct phenotypes on aortic and ventricular sides.
- The aortic side, susceptible to sclerosis, shows balanced propathological and protective pathways.
- Understanding endothelial phenotype balance is key to early aortic valve sclerosis detection.
Purpose of the Study:
- To investigate side-specific endothelial gene expression in early aortic valve sclerosis.
- To determine the endothelial phenotype response to hypercholesterolemia in a large animal model.
Main Methods:
- Adult male swine were fed hypercholesterolemic or normal diets for 2 weeks and 6 months.
- Transcript profiling analyzed differential gene expression in aortic and ventricular valve endothelial populations.
- Pathway analysis identified key biological pathways involved in the endothelial response.
Main Results:
- Hypercholesterolemia induced lipid insudation on the aortic side of leaflets.
- The aortic side showed significantly higher differential gene expression (1,325 genes) compared to the ventricular side (87 genes) after 2 weeks.
- Pathway analysis revealed differential expression of protective pathways (e.g., PPAR-gamma, NF-kappaB) on the susceptible aortic side, confirmed at the protein level.
Conclusions:
- Aortic valve endothelium on the pathosusceptible side is responsive to hypercholesterolemia.
- Transcriptional profiles indicate an induced and persistent protective endothelial phenotype on the side prone to aortic valve sclerosis.
Unlabelled:
Background- The endothelium of healthy aortic valves expresses different phenotypes on the aortic and ventricular sides. On the aortic side, which is susceptible to aortic valve sclerosis, there is a balanced coexpression of both propathological and protective pathways. Side-specific global gene expression can address endothelial phenotype balance in early aortic valve sclerosis.
Methods And Results:
Adult male swine were fed a hypercholesterolemic or an isocaloric normal diet for 2-week and 6-month periods. Hypercholesterolemia induced localized lipid insudation confined to the aortic side of the leaflet. Transcript profiling of valve endothelial populations showed that the susceptible aortic side was more sensitive to 2-week hypercholesterolemia than the ventricular side (1,325 vs 87 genes were differentially expressed). However, greater sensitivity was not evidence of a dysfunctional phenotype. Instead, pathway analyses identified differential expression of caspase 3-, peroxisome proliferator-activated receptor gamma-, TNF-alpha-, and nuclear factor-kappaB-related pathways that were consistent with a protective endothelial phenotype. This was confirmed at the protein level at 2 weeks and persisted at 6 months.
Conclusions:
In a large animal model at high spatial resolution, endothelium on the pathosusceptible side of the aortic valve leaflet is responsive to hypercholesterolemia. Transcript profiles indicative of a protective phenotype were induced and persisted on the side prone to aortic valve sclerosis.
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